US9717726B2 - Product and method for treating diarrhea - Google Patents

Product and method for treating diarrhea Download PDF

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US9717726B2
US9717726B2 US14/209,937 US201414209937A US9717726B2 US 9717726 B2 US9717726 B2 US 9717726B2 US 201414209937 A US201414209937 A US 201414209937A US 9717726 B2 US9717726 B2 US 9717726B2
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receptor antagonist
diarrhea
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cetirizine
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US20140275116A1 (en
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II Reed B Hogan
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Maregade Rx LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • Diarrhea is a common condition characterized by increased frequency or fluidity of bowel movements. Diarrhea may cause dehydration and electrolyte abnormalities that may require hospitalization to replace lost fluids and electrolytes until the symptoms subside. Persistent, uncontrolled diarrhea can cause such severe malnutrition, electrolyte imbalances and dehydration that it may ultimately result in death. Acute diarrhea is usually treated with fluid and electrolyte replacement, dietary modifications and antidiarrheal or antimicrobial agents. Acute diarrhea complications may cause severe illness, especially in high-risk groups, for example patients with underlying immunosuppression or advanced age. Antidiarrheal treatment is also required in patients with chronic diarrhea. Empiric therapies routinely used for chronic diarrhea include: stool-modifying agents (such as psyllium and fiber), anticholinergic agents, opiates, antibiotics, and probiotics.
  • stool-modifying agents such as psyllium and fiber
  • anticholinergic agents such as psyllium and fiber
  • opiates such as
  • Chronic diarrhea may be a symptom of a chronic disease, for example irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome
  • IBS alone is estimated to affect 15-20% of the U.S. population, and accounts for at least 30% of all gastroenterology health care costs.
  • the cause of the chronic diarrhea is not found, the diagnosis remains uncertain, and empiric treatments unsuccessful.
  • antidiarrheal agents that effectively stop or greatly reduce bowel movements and fluid loss in patients undergoing treatment, to remove the cause of diarrhea, or in patients in which the cause of diarrhea is not found.
  • H1 and H2 receptor antagonists are two classes of antihistamines.
  • H1 receptor antagonists are used in the symptomatic treatment of multiple conditions, including allergic rhinoconjunctivitis, relief of pruritus in patients with urticaria, and in patients with chronic asthma.
  • Newer H1 receptor antagonists such as cetirizine, are referred to as second-generation H1 receptor antagonists, and are more selective for peripheral H1 receptors than first-generation H1 receptor antagonist, which antagonize both the central and peripheral nervous system H1 receptors as well as cholinergic receptors.
  • the selectivity significantly reduces the occurrence of adverse drug reactions, such as sedation, while still providing effective relief of allergic conditions.
  • H2 receptor antagonists are used primarily to treat symptoms of acid reflux, or gastroesophageal reflux disease. H2 receptor antagonists reduce the production of stomach acid. Often diarrhea is listed as a major side effect of H2 receptor antagonists.
  • Diphenhydramine a first-generation H1 receptor antagonist, together with either cimetidine or ranitidine, H2 receptor antagonists, have been studied for the treatment of acute allergic reactions.
  • H1 receptor antagonists a first-generation H1 receptor antagonist, together with either cimetidine or ranitidine, H2 receptor antagonists, have been studied for the treatment of acute allergic reactions.
  • a first study (Runge et al. “Histamine antagonists in the treatment of acute allergic reactions” Ann Emerg Med (March 1992) 21:237-242)
  • patients were treated by a single intravenous administration of a solution 300 mg cimetidine and placebo, 50 mg diphenhydramine and placebo, or diphenhydramine plus cimetidine; the treatment was found effective for acute urticaria.
  • a second study Lidimetidine
  • the present invention is a method of treating diarrhea in a patient, comprising administering an H1 receptor antagonist and an H2 receptor antagonist to the patient.
  • the H1 receptor antagonist comprises cetirizine and the H2 receptor antagonist comprises famotidine.
  • the present invention is a method of treating diarrhea in a patient, comprising administering an H1 receptor antagonist and an H2 receptor antagonist to the patient.
  • the H2 receptor antagonist is not ranitidine.
  • the present invention is a method of treating diarrhea in a patient, comprising administering an H1 receptor antagonist and an H2 receptor antagonist to the patient.
  • the present invention is a method of treating diarrhea in a patient, comprising administering an H1 receptor antagonist and an H2 receptor antagonist to the patient.
  • the patient does not have mastocytic enterocolitis.
  • the present invention is a pharmaceutical composition for treating diarrhea, comprising an H1 receptor antagonist, and an H2 receptor antagonist.
  • the H2 receptor antagonist is not ranitidine
  • the pharmaceutical composition is an oral dosage form.
  • the present invention is a pharmaceutical composition for treating diarrhea, comprising an H1 receptor antagonist, and an H2 receptor antagonist.
  • the H1 receptor antagonist is not diphenhydramine.
  • the present invention is a pharmaceutical composition for treating diarrhea in a patient, comprising an H1 receptor antagonist, and an H2 receptor antagonist.
  • the patient does not have mastocytic enterocolitis.
  • the present invention is use of an H1 receptor antagonist and an H2 receptor antagonist for the preparation of a medicament for treating a patient having diarrhea.
  • diarrhea means increased fluidity or frequency of stools.
  • acute diarrhea is ongoing diarrhea which has occurred for at most 4 weeks.
  • chronic diarrhea is ongoing diarrhea for more than 4 weeks.
  • unit dosage form means a single pre-measured dose, and includes tablets, pills, capsules, packets, suspensions, transdermal patches, and rectal suppositories.
  • FIG. 1 illustrates participants and responses by treatment group of an IBS-D study.
  • the present invention makes use of the discovery that administering an H1 receptor antagonist and an H2 receptor antagonist to a patient, results in a significant reduction or cessation of diarrhea.
  • Applicant discovered that the combination of an H1 receptor antagonist and an H2 receptor antagonist administered to patients with diarrhea, resulted in 85-90% positive responders (see Example 7 and Table 1).
  • a positive responder is identified as having a 50% or more reduction in the number of stools per day or a change in stool formation from liquid to solid. No adverse reactions or events were reported.
  • a control group was treated with fiber (Metamucyl®) and an anticholinergic (Bentyl®); positive responders in the control group were less than 25%.
  • the present invention includes treating diarrhea by administering an H1 receptor antagonist and an H2 receptor antagonist in combination.
  • the present invention also includes unit dosage forms, multi-dosage forms, and kits, including an H1 receptor antagonist and an H2 receptor antagonist.
  • the H1 receptor antagonist includes cetirizine and the H2 receptor antagonist includes famotidine.
  • Diarrhea may be acute or chronic. Diarrhea may also be further classified:
  • IBS associated diarrhea a chronic diarrhea
  • IBS-diarrhea predominate a chronic diarrhea
  • IBS-D IBS-diarrhea predominate
  • the patient does not have mastocytic enterocolitis.
  • H1 receptor antagonists block H1 histamine receptors; first-generation H1 receptor antagonists block histamine receptors in the central and peripheral nervous systems, as well as cholinergic receptors, while second-generation H1 receptor antagonists are selective for H1 histamine receptors in the peripheral nervous system.
  • First-generation H1 receptor antagonists include brompheniramine, chlorpheniramine, dexbrompheniramine, dexchlorpheniramine, pheniramine, triprolidine, carbinoxamine, clemastine, diphenhydramine, pyrilamine, promethazine, hydroxyzine, azatadine, cyproheptadine, and phenindamine.
  • Second-generation H1 receptor antagonists include ketotifen, rupatadine, mizolastine, acrivastine, ebastine, bilastine, bepotastine, terfenadine, quifenadine, azelastined, cetirizine, levocetirizine, desloratadine, fexofenadine and loratadine.
  • the H1 receptor antagonist is a second-generation H1 receptor antagonist, more preferably the H1 receptor antagonist is cetirizine or levocetirizine, with cetirizine being particularly preferred. Mixtures and combination of H1 receptor antagonists may also be used.
  • the H1 receptor antagonists may be used in an amount of from 0.1 to 10 times the amount typically used for the treatment of allergies, for example in an amount of 0.1 to 600 mg per dose, 0.5 to 500 mg per dose, 1.0 to 50 or 60 mg per dose, including 1.25, 1.5, 1.75, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40 and 45 mg per dose.
  • the H1 receptor antagonist is administered 1, 2, 3 or 4 times per day.
  • the H1 receptor antagonist may be administered as an injectable formulation, for example intravenously, intraparenterally or intramuscularly; transdermally, via a transdermal patch; or, preferably, orally, as a powder, table or capsule, an oral solution or suspension, or sublingual or buccal tablets.
  • injectable formulation for example intravenously, intraparenterally or intramuscularly; transdermally, via a transdermal patch; or, preferably, orally, as a powder, table or capsule, an oral solution or suspension, or sublingual or buccal tablets.
  • Alternative forms of administration include rectal suppositories, inhaled, epidural, subcutaneous, nasal spray, transmucosal, and intradermal formulations.
  • H2 receptor antagonists block H2 histamine receptors.
  • H2 receptor antagonists include cimetidine, ranitidine, famotidine, and nizatidine, with famotidine being preferred. Mixtures and combinations of H2 receptor antagonists may also be used.
  • the H2 receptor antagonists may be used in an amount of from 0.1 to 10 time the amount typically used for treatment dyspepsia, for example 1.0 to 8000 mg per dose, 2.0 to 1000 mg per dose, 5.0 to 800 mg per dose, including 6.0, 7.0, 8.0, 9.0, 10, 15, 20, 21, 22, 22.5, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 120, 140, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, and 700 mg per dose.
  • the H2 receptor antagonist is administered 1, 2, 3 or 4 times per day.
  • the H2 receptor antagonist may be administered as an injectable formulation, for example intravenously, intraparenterally or intramuscularly; transdermally, via a transdermal patch; or, preferably, orally, as a powder, table or capsule, an oral solution or suspension, or sublingual or buccal tablets.
  • injectable formulation for example intravenously, intraparenterally or intramuscularly; transdermally, via a transdermal patch; or, preferably, orally, as a powder, table or capsule, an oral solution or suspension, or sublingual or buccal tablets.
  • Alternative forms of administration include rectal suppositories, inhaled, epidural, subcutaneous, nasal spray, transmucosal, and intradermal formulations.
  • Treatment should be carried out for an amount of time to resolve any underlying cause in the case of acute diarrhea, for example 3 to 14 days, or 5 to 10 days.
  • any underlying cause in the case of acute diarrhea for example 3 to 14 days, or 5 to 10 days.
  • chronic diarrhea a 30 day trial is reasonable, and if the underlying cause of the diarrhea cannot be resolved, for example in the case of IBS-D, then treatment should be continued indefinitely.
  • the H1 and H2 receptor antagonists are administered simultaneously, as a unit dosage form containing both receptor antagonists.
  • unit dosage forms include oral compositions, such as tablets (for example, sublingual or buccal tablets), capsules (for example, hard gelatin and soft gelatin capsules), transmucosal and sublingual patches and films, pre-measured powder packets and saches, flavored and/or sweetened aqueous solutions or suspensions. Because diarrhea is often associated with dehydration, flavored and/or sweetened aqueous solutions or suspension may be oral rehydration solutions, or solutions which also contain sodium and glucose or a glucose-containing saccharide, in amounts of 250 ml, 500 ml or 1 liter of fluid.
  • a pre-measured powder packet containing the receptor antagonists, together with sodium (for example, as sodium chloride) and glucose or a glucose-containing saccharide, and optionally other excipients, flavorings and/or sweeteners, may be provided, which may be readily mixed with water prior to consumption.
  • the oral unit dosage form is present as a once-per-day dosage.
  • oral dosage forms include a tablet containing famotidine, in an amount of 5, 10, 15, 20, 22.5, 25, 30, 35 or 40 mg, as a core, and a coating of cetirizine, in an amount of 2.5, 5, 8.5, 10, 15, or 20 mg.
  • a capsule containing granules of famotidine and cetirizine in water-soluble matrix In another example, both the famotidine and the cetirizine are present as a mixture in a matrix, either as a table or within a capsule.
  • other H1 and/or H2 receptor antagonists may be used in place of, or in addition to, famotidine and/or cetirizine.
  • unit dosage forms may also be provided, containing both H1 and H2 receptor antagonist.
  • injectable formulation containing a sterile solution or suspension including formulation for administration intravenously, intraparenterally or intramuscularly, may be provided.
  • a unit dosage form for administration transdermally, via a transdermal patch may be provided.
  • Other unit dosage forms include rectal suppositories, inhaled, epidural, subcutaneous, nasal spray, and intradermal formulations. Excipients and adjuvants maybe also be included in any of the unit dosage forms, both oral and non-oral.
  • Multi-dosage forms such as kits, containing 2 to 30, 3 to 25, or 5 to 14 unit dosage forms, for example 6, 7, 8, 9, 10, 11, 12, 13, 15, 20, 40, 50 or 60 unit dosage forms, may be provided.
  • the multi-dosage forms contain sufficient unit dosage forms for administration over a period of 2 to 30, 3 to 25, or 7 to 14 days, for example 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 20 or 30 days.
  • Kits may also be provided, which include oral rehydration solutions, or powders which may be hydrated to form oral rehydration solutions, or kits containing sodium and glucose or a glucose-containing saccharide, as well as other excipients, flavorings and/or sweeteners, together with unit dosage forms.
  • Patient #1 age 65, was hospitalized for more than one week for weight and fluid loss related to chronic diarrhea.
  • the patient had from 20 to 40 stools per day and severe life threatening diarrhea.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Symptoms subsided within 48 hours with a 95% decrease in the number of stools and the patient was discharged.
  • the patient responded to treatment and now has 1 stool per day, occasionally two, but no diarrhea.
  • Patient #1 age 80, with mild to severe cramping and 4 to 5 stools a day.
  • the patient was treated with 300 mg ranitidine and 10 mg cetirizine, once per day.
  • the patient reported a 60% reduction in the number of stools.
  • Patient #2 age 62, had severe weight loss, greater than 30 pounds, related to the diarrhea, 10 to 20 stools per day, and was opiate and steroid dependant.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful with an 85 to 90% reduction in the number of stools.
  • the patient now has 1 to 2 stools per day for over 8 months on treatment.
  • Patient #3 age 65, prior to treatment was homebound, had 4 to 5 stools per day, each episode lasting an hour or two.
  • the patient was treated with 300 mg ranitidine and 10 mg cetirizine, once per day. Treatment was successful, with the patient reporting a 90% reduction in the number of stools.
  • Patient #4 age 67, with moderate diarrhea and cramping, had 4 to 5 stools per day.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful, with a 75% reduction in the number of stools, no cramping and no side effects.
  • Patient #5 age 26, had moderate to severe diarrhea with 7 to 8 stools per day.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 50%, down to 3 to 4 per day, with no side effects.
  • Patient #6 age 74, with severe diarrhea, had 8 stools per day and was homebound.
  • the patient was treated with 300 mg ranitidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 75%, down to 2 stools per day and no side effects. Patient is presently only on cetirizine.
  • Patient #7 age 51, with colon resection, had severe diarrhea with 15 to 20 stools per day.
  • the patient was treated with 300 mg ranitidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 94%, to 1 to 2 stools per day and better consistency, with no side effects.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 70%, to 1 to 2, mostly 1, per day and a repeat colonoscopy was cancelled because symptoms had resolved.
  • Patient age 64, with colon cancer and moderate to severe diarrhea, in a deconditioned state from chemotherapeutic agents, had 5 to 10 stools per day.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 80%, to 1 to 2 per day and normal consistency, with no side effects.
  • Patient #1 age 64, with Crohn's disease, had 12 to 15 stools per day and severe diarrhea.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was not successful, with a decrease in the number of stools only by 5%. There were no side effects.
  • Patient #2 age 37, with Crohn's disease and colitis, had severe diarrhea with 4 to 5 stools per day.
  • the patient was treated with 300 mg ranitidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 75%, to one stool per day and normal consistency. There were no side effects.
  • Patient #3 age 35, with ulcerative colitis, had severe diarrhea with 4 to 6 stools per day.
  • the patient was treated with 20 mg famotidine and 10 mg cetirizine, once per day. Treatment was successful, with a decrease in the number of stools by 50%. There were no side effects.
  • Patient #1 age 57, with celiac disease had mild to moderate diarrhea, with 2 to 4 stools per day. The patient had no improvement from treatment with 20 mg famotidine and 10 mg cetirizine, once per day. There were no side effects.
  • Patient #2 age 26, with celiac disease. The patient had little improvement from treatment.
  • the study population age was 18 to 80, with the patients having chronic unexplained diarrhea from an outpatient population of a clinic and outpatients from a medical center, who gave consent for treatment. Patients were excluded who had a history of systemic or cutaneous mastocytosis, definable etiology of diarrhea (other than IBS-D or chronic idiopathic diarrhea) such as celiac disease, inflammatory bowel disease, or lactose intolerance, or who were pregnant. The study was initiated after IRB approval.
  • One study arm received famotidine (20 mg per day) and cetirizine (10 mg per day), once per day.
  • the second study arm received fiber (Metamucil®) and an anticholinergic (Bentyl®) once per day.
  • Table 1 shows the results of the study.
  • Tables 2 and 3 show the statistical analysis of the study results.
  • FIG. 1 illustrates participants and responses by treatment group.
  • the bars on the left represent the patients who received famotidine and cetirizine, while the bars on the right represent the patients who received fiber and anticholinergic.
  • 90% of the patients receiving famotidine and cetirizine responded to the treatment, while only 10% of those receiving fiber and anticholinergic responded to the treatment.
  • Tables 4 and 5 show the percent decrease in number of stools per day, for the famotidine and cetirizine study arm, and the dicyclomine and psyllium study arm, respectively.
  • the study population age was 21 to 70, with patients diagnosed with chronic diarrhea, who gave consent for treatment. Patients were excluded if there was a sensitivity or allergy to H1 receptor antagonists or H2 receptor antagonists, renal impairment or a history of renal failure, a diagnosis of inflammatory bowel disease (Crohn's disease or ulcerative colitis), a known active infection of the colon (such as Clostridium difficile, giardia , or Salmonella ), biopsy proven microscopic colitis (collagenous or lymphocytic colitis), or an inability to discontinue other anti-diarrheal agents during the study. Patients were also excluded if they were pregnant or lactating women, or if the patient was taking atazanavir, itraconazole, or ketoconazole. The study was initiated after IRB approval.
  • the “active” group received famotidine (24 mg) and cetirizine (9 mg), once per day, with both drugs combined in the form of a single capsule.
  • the “placebo” group received a capsule once per day, which contained no active ingredients.
  • the results of the study are shown in Table 6.
  • the table shows the results of 27 patients, 12 in the placebo group and 15 in the active group.
  • the average value for percent change is stools per day (SPD) was 25.08 for the placebo group, while the average value for percent change in SPD was 46.00 for the active group.
  • SPD stools per day
  • SPD placebo group
  • the data demonstrate a clinical significance between the placebo group and the active group, and demonstrate a significant improvement in the quality of life of the patients in the active group.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10034875B2 (en) * 2013-03-14 2018-07-31 Maregrade RX, LLC Product and method for treating diarrhea
US11419868B2 (en) 2016-12-23 2022-08-23 White Sands Pharma Llc Low dose product and method for treating diarrhea

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015073573A1 (fr) * 2013-11-14 2015-05-21 Jacobs Michael M Compositions et méthodes de prévention et de traitement du syndrome de la xylostomiase induite par l'alcool
IT201900012645A1 (it) * 2019-07-23 2021-01-23 Eros Zanotti Una composizione farmaceutica per l'uso nel trattamento delle chinetosi
CN117293008A (zh) * 2019-08-05 2023-12-26 株式会社日立高新技术 等离子处理装置
WO2023049205A1 (fr) * 2021-09-22 2023-03-30 Hista Rx Llc Compositions et méthodes de traitement et de prévention de la cystite interstitielle

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001792A1 (fr) 1993-07-06 1995-01-19 Merck & Co., Inc. Composes anti-h2-antihistaminiques
US20090312358A1 (en) 2006-03-22 2009-12-17 Trustees Of Boston University Method for management of diarrhea
US20100144718A1 (en) 2006-04-07 2010-06-10 Michalis Nicolaou Treatment of diseases modulated by a h4 receptor agonist
US8207292B2 (en) 2007-02-12 2012-06-26 Michalis Nicolaou Treatment of COPD, gastro-esophageal reflux disease (GERD), food allergies and other gastrointestinal conditions and disorders ameliorated by proper histamine management using a combination of histidine decarboxylase inhibitors, LRA drugs, anti-H1 and/or anti-H2 drugs
WO2014152420A2 (fr) 2013-03-14 2014-09-25 Maregade Rx, LLC Produit et procédé pour le traitement de diarrhée

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5204118A (en) 1989-11-02 1993-04-20 Mcneil-Ppc, Inc. Pharmaceutical compositions and methods for treating the symptoms of overindulgence
US6264984B1 (en) * 1999-12-06 2001-07-24 Bristol-Myers Squibb Company Effervescent histamine H2 antagonist composition
US6656492B2 (en) * 2000-06-30 2003-12-02 Yamanouchi Pharmaceutical Co., Ltd. Quick disintegrating tablet in buccal cavity and manufacturing method thereof
RU2281326C2 (ru) 2000-11-30 2006-08-10 Дзе Байо Бэлэнс Корп. ШТАММ БАКТЕРИЙ Escherichia coli, ПРЕДНАЗНАЧЕННЫЙ ДЛЯ НОРМАЛИЗАЦИИ ФИЗИОЛОГИЧЕСКОЙ АКТИВНОСТИ ЖЕЛУДОЧНО-КИШЕЧНОГО ТРАКТА, ПРОБИОТИЧЕСКАЯ КОМПОЗИЦИЯ, ПРЕДНАЗНАЧЕННАЯ ДЛЯ НОРМАЛИЗАЦИИ ФИЗИОЛОГИЧЕСКОЙ АКТИВНОСТИ ЖЕЛУДОЧНО-КИШЕЧНОГО ТРАКТА (ВАРИАНТЫ), И СПОСОБ ЕЕ ПОЛУЧЕНИЯ, СПОСОБ ВЫРАЩИВАНИЯ ШТАММА БАКТЕРИЙ Escherichia coli И ПИЩЕВОЙ ПРОДУКТ
KR100967601B1 (ko) * 2001-11-23 2010-07-05 얀센 파마슈티카 엔.브이. 두개내압의 상승을 신속히 감소시키기 위한 항-히스타민제의 용도
SE528789C2 (sv) 2004-09-10 2007-02-13 Sandvik Intellectual Property PVD-belagt skär av hårdmetall samt sätt att tillverka detta
US20070077300A1 (en) * 2005-09-30 2007-04-05 Wynn David W Oral compositions containing a salivation inducing agent
US20070254050A1 (en) * 2006-05-01 2007-11-01 Quart Barry D Method for treatment of diarrhea-predominant irritable bowel syndrome
US20090042972A1 (en) * 2006-05-19 2009-02-12 Somaxon Pharmaceuticals, Inc. Methods of using low-dose doxepin for the improvement of sleep
CA2721133C (fr) * 2007-04-13 2018-11-06 Somaxon Pharmaceuticals, Inc. Formulations de doxepine a faible dose et procede de preparation et d'utilisation de celle-ci
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US9856477B2 (en) 2012-11-13 2018-01-02 Codiak Biosciences, Inc. Delivery of therapeutic agent
WO2018119464A1 (fr) 2016-12-23 2018-06-28 Maregade Rx, LLC Produit à faible dose et méthode de traitement de la diarrhée

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995001792A1 (fr) 1993-07-06 1995-01-19 Merck & Co., Inc. Composes anti-h2-antihistaminiques
US20090312358A1 (en) 2006-03-22 2009-12-17 Trustees Of Boston University Method for management of diarrhea
US20100144718A1 (en) 2006-04-07 2010-06-10 Michalis Nicolaou Treatment of diseases modulated by a h4 receptor agonist
US8207188B2 (en) 2006-04-07 2012-06-26 Michalis Nicolaou Treatment of diseases modulated by a H4 receptor agonist
US8207292B2 (en) 2007-02-12 2012-06-26 Michalis Nicolaou Treatment of COPD, gastro-esophageal reflux disease (GERD), food allergies and other gastrointestinal conditions and disorders ameliorated by proper histamine management using a combination of histidine decarboxylase inhibitors, LRA drugs, anti-H1 and/or anti-H2 drugs
WO2014152420A2 (fr) 2013-03-14 2014-09-25 Maregade Rx, LLC Produit et procédé pour le traitement de diarrhée

Non-Patent Citations (139)

* Cited by examiner, † Cited by third party
Title
"Diarrhea", National Digestive Diseases Information Clearinghouse, pp. 1-8, (2011).
"Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trails for Therapeutics in Adult Healthy Volunteers", U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Pharmacology and Toxicology, 30 pages, (2005).
"H2 blockers (acid reducers) for gastroesophageal reflux disease (GERD)", found at www.webmd.com/heartburn-gerd/h2-blockers-acid-reducers-for-gastroesophageal-reflux-disease-gerd, 2 pages, printed on Feb. 11, 2013.
"How are mast cell issues treated?", Microscopic Colitis Support, 5 pages, found at www.microscopiccolitis.org/articles/How%20are%20mast%20cell%20issues%20treated.html, Apr. 6, 2013.
"Mast cell" found at http://en.wikipedia.org/wiki/Mast-cell, 5 pages, (2014).
"Mast cell" found at http://en.wikipedia.org/wiki/Mast—cell, 5 pages, (2014).
13 Pages, Mar. 18, 2016, 14722445.5, EP.
22 Pages, Oct. 9, 2014, PCT/US2014/027323, PCT.
9 Pages, Jun. 24, 2014, PCT/US2014/027323, PCT.
Ahrens, R. et al., "Histamine-induced chloride secretion is mediated via H2-receptors in the pig proximal colon", Inflammation Research, vol. 52, issue 2, pp. 79-85, (2003).
Akhavein, A. et al., "Allergic mastocytic gastroenteritis and colitis: an unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility", Gastroenterology Research and Practice, pp. 1-6, (2012).
Akin, C. et al., "Mast cell activation syndrome: Proposed diagnostic criteria", Journal of Allergy and Clinical Immunology, vol. 126, No. 6, pp. 1099-1104, (2010).
Aly, A. et al., "Effect of an H2-receptor blocking agent on diarrhoeas after extensive small bowel resection in crohn's disease", Acta Medica Scandinavica, vol. 207, No. 1-2, pp. 119-122, (1980).
American Gastroenterological Association, "American Gastroenterological Association medical position statement: Guidelines for the evaluation and management of chronic diarrhea", Gastroenterology, vol. 116, pp. 1461-1463, (1999).
Arevalo, F. et al., "Increase of intraepithelial lymphocytes in patients with irritable bowel syndrome", Rev. Gastroenterology Peru, vol. 31, No. 4, pp. 315-318, (2011), English Abstract.
Baker, E.H. et al., "Complications of laxative abuse", Annual Review of Medicine, vol. 47, pp. 127-134, (1996).
Barbara, G. et al., "Functional gastrointestinal disorders and mast cells: implications for therapy", Neurogastroenterology and Motility, vol. 18, pp. 6-17, (2006).
Barbara, G. et al., "Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome", Gastroenterology, vol. 132, issue 1, pp. 26-37, (2007).
Barbara, G. et al., "New pathophysiological mechanisms in irritable bowel syndrome", Alimentary Pharmacology & Therapeutics, vol. 20, supplement 2, pp. 1-9, (2004).
Berry, E.M. et al., "Carcinoid myopathy and treatment with cyproheptadine (Periactin)", Gut, vol. 15, pp. 34-38, (1974).
Bleehan, S.S. et al., "Cimetidine and chlorpheniramine in the treatment of chronic idiopathic urticaria: a multi-centre randomized double-blind study", British Journal of Dermatology, vol. 117, issue 1, pp. 81-88, (1987).
Boyce, P.M. et al., "Irritable bowel syndrome according to varying diagnostic criteria: are the new Rome II criteria unnecessarily restrictive for research and practice?", American Journal of Gastroenterology, vol. 95, issue 11, pp. 3176-3183, (2000).
Braak, B. et al., "Mucosal immune cell numbers and visceral sensitivity in patients with irritable bowel syndrome: is there any relationship?", American Journal of Gastroenterology, vol. 107, pp. 715-726, (2012).
Breunig, E. et al., "Histamine excites neurones in the human submucous plexus through activation of H1, H2, H3 and H4 receptors", The Journal of Physiology, vol. 583, pt. 2, pp. 731-742, (2007).
Chey, W.D. et al., "Utility of the Rome I and Rome II criteria for irritable bowel syndrome in US women", American Journal of Gastroenterology, vol. 97, No. 11, pp. 2803-2811, (2002).
Coupet, J. et al., "Brain histamine H1- and H2-receptors and histamine-sensitive adenlate cyclase: effects of antipsychotics and antidepressants", European Journal of Pharmacology, vol. 74, pp. 149-155, (1981).
De Ponti, F., "Drug development for the irritable bowel syndrome: current challenges and future perspectives", Frontiers in Pharmacology, vol. 4, article 7, pp. 1-12, (2013).
Deiteren, A. et al., "Histamine H4 and H1 receptors contribute to postinflammatory visceral hypersensitivity", Gut, vol. 63, No. 12, pp. 1873-1882, (2014).
del Cuvillo, A. et al., "Comparative pharmacology of the H1 antihistamines", Journal of Investigational Allergology and Clinical Immunology, vol. 16, supplement 1, pp. 3-12, (2006).
Deml, K-F., et al., "Interactions of histamine H1-receptor agonists and antagonists with the human histamine H4-receptor", Molecular Pharmacology, vol. 76, No. 5, pp. 1019-1030, (2009).
DeSilva, A.P. et al., "Subclinical mucosal inflammation in diarrhea-predominant irritable bowel syndrome (IBS) in a tropical setting", Scandinavian Journal of Gastroenterology, vol. 47, No. 6, pp. 619-624, (2012).
Di Fiore et al. (Best Practice & Research Clinical Gastroenterology 23 (2009) 113-124). *
Dorsch, W., et al., "Histamine1-histamine2 antagonism: effect of combined clemastine and cimetidine pretreatment on allergen and histamine-induced reactions of the guinea pig lung in vivo and in vitro", Agents and Actions, vol. 12, issue 1-2, pp. 113-118, (1982).
Dunlop, S.P. et al., "Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes", American Journal of Gastroenterology, vol. 101, No. 6, pp. 1288-1294, (2006).
DuPont, H.L. et al., "Diarrhea", National Digestive Diseases Information Clearinghouse, 8 pages, Jan. 2012.
Echizen, H., et al., "Clinical pharmacokinetics of famotidine", Clinical Pharmacokinetics, vol. 21, issue 3, pp. 178-194, (1991).
Elvevi, A., et al., "Severe chronic diarrhea and maculopapular rash: A case report", World Journal of Gastroenterology, vol. 17, issue 34, pp. 3948-3952, (2011).
European Search Report dated Oct. 31, 2016, for EP application No. 14 722 445.5-1466, 5 pages.
Farhadi, A. et al., "Mucosal mast cells are pivotal elements in inflammatory bowel disease that connect the dots: stress, intestinal hyperpermeability and inflammation", World Journal of Gastroenterology, vol. 13, No. 22, pp. 3027-3030, (2007).
Fasano, A., "Zonulin and its regulation of intestinal barrier function: The biological door to inflammation, autoimmunity, and cancer", Physiological Reviews, vol. 91, pp. 151-175, (2011).
Fedorowicz, Z. et al., "Histamine H2-receptor antagonists for urticaria (review)", Cochrane Database of Systematic Reviews, Issue 3, pp. 1-35, (2012).
Fine, K.D. et al., "AGA technical review on the evaluation and management of chronic diarrhea", Gastroenterology, vol. 116, issue 6, pp. 1464-1486, (1999).
Flockhart, D.A. et al., "Selection of drugs to treat gastro-oesophageal reflux disease: the role of drug interactions", Clinical Pharmacokinetics, vol. 39, issue 4, pp. 295-309, (2000).
Fogel, W.A. et al., "Histamine in idiopathic inflammatory bowel diseases-not a standby player", Folia Medica Cracoviensia, vol. 46, No. 3-4, pp. 107-118, (2005).
Fogel, W.A. et al., "Histamine in idiopathic inflammatory bowel diseases—not a standby player", Folia Medica Cracoviensia, vol. 46, No. 3-4, pp. 107-118, (2005).
Fondacaro, J.D. et al., "Cecectomized rat-A model of experimental secretory diarrhea in conscious animals", Journal of Pharmacological Methods, vol. 24, pp. 59-71, (1990).
Fondacaro, J.D. et al., "Cecectomized rat—A model of experimental secretory diarrhea in conscious animals", Journal of Pharmacological Methods, vol. 24, pp. 59-71, (1990).
Forbes, D.A. et al., "Laxative abuse and secretory diarrhoea", Archives of Disease in Childhood, vol. 60, No. 1, pp. 58-60, (1985).
Ford, A.C. et al., "Mucosal inflammation as a potential etiological factor in irritable bowel syndrome: a systematic review", Journal of Gastroenterology, vol. 46, No. 4, pp. 421-431, (2011).
Fordtran, J.S. et al., "Pathophysiology of chronic diarrhoea: insights derived from intestinal perfusion studies in 31 patients", Clinics in Gastroenterology, vol. 15, No. 3, pp. 477-490, (1986).
Friedling, T. et al., "Diabetic autonomic neuropathy of the gastrointestinal tract", UpToDate, 13 pages, Mar. 2016.
Guarino, B., "Abuse of diarrhea medicine you know well is alarming physicians", The Washington Post, Morning Mix, 3 pages, found at www.washingtonpost.com/news/rnorning-mix/wp/2016/05/04/physicians-alarmed-by-abuse-of-over-the-counter-diarrhea-medicine-you-know-well/, May 4, 2016.
Halvorson, H.A. et al., "Postinfectious irritable bowel syndrome-a meta-analysis", American Journal of Gastroenterology, vol. 101, pp. 1894-1899, (2006).
Hamilton, M.J. et al., "Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations", Journal of Allergy and Clinical Immunology, vol. 128, No. 1, pp. 147-152, (2011).
Harvey, R.P. et al., "The effect of H1 and H2 blockade on cutaneous histamine response in man", The Journal of Allergy and Clinical Immunology, vol. 65, issue 2, pp. 136-139, (1980).
He, S. et al., "Formulation and evaluation of novel coated floating tablets of bergenin and cetirizine dihydrochloride for gastric delivery", Drug Development and Industrial Pharmacy, vol. 38, No. 10, pp. 1280-1288, (2012).
Hofstra, C.L. et al., "Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells", The Journal of Pharmacology and Experimental Therapeutics, vol. 305, No. 3, pp. 1212-1221, (2003).
Humphries, T.J. et al. "Review article: drug interactions with agents used to treat acid-related diseases", Alimentary Pharmacology & Therapeutics, vol. 13, supplement 3, pp. 18-26, (1999).
International Search Report dated Jun. 24, 2014, for PCT application No. PCT/US2014/027323, 9 pages.
International Search Report dated Oct. 9, 2014, for PCT application No. PCT/US2014/027323, 22 pages.
Irwin, R.B. et al., "Mediator release in local heat urticaria: protection with combined H1 and H2 antagonists", The Journal of Allergy and Clinical Immunology, vol. 76, issue 1, pp. 35-39, (1985).
Ishikawa, M. et al., "Drug interaction effects on antitumor drugs. XIII. Amelioration of cisplatin lethality and renal toxicity by chlorpromazine in mice", Biological & Pharmaceutical Bulletin, vol. 16, No. 11, pp. 1104-1107, (1993).
Jakate, S. et al., "Mastocytic enterocolitis increased mucosal mast cells in chronic intractable diarrhea", Archives of Pathology & Laboratory Medicine, vol. 130, pp. 362-367, (2006).
Juckett, G. et al., "Evaluation of chronic diarrhea", American Family Physician, vol. 84, No. 10, pp. 1119-1126, (2011).
Kirsch, R.H. et al., "Histopathological alterations in irritable bowel syndrome", Modern Pathology, vol. 19, pp. 1638-1645, (2006).
Klooker, T.K. et al., "The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome", Gut, vol. 59, pp. 1213-1221, (2010).
Krishnamurthi, S.S., "Enterotoxicity of chemotherapeutic agents", UpToDate, 15 pages, Mar. 2016.
Kristjansson, G. et al., "Clinical and subclinical intestinal inflammation assessed by the mucosal patch technique: studies of mucosal neutrophil and eosinophil activation in inflammatory bowel diseases and irritable bowel syndrome", Gut, vol. 53, pp. 1806-1812, (2004).
Kushnir-Sukhov, N.M. et al., "Mastocytosis", Allergy and Allergic Disease, 2nd edition, chapter 91, pp. 1878-1893, (2008).
Kushnir-Sukhov, N.M. et al., "Mastocytosis", Allergy and Allergic Diseases, Second Edition, pp. 1878-1893, (2009).
Lever, D.S. et al., "Acute Diarrhea", Cleveland Clinic, Center for Continuing Education publications: Disease Management Project, pp. 1-8, (2010).
Lewis, J,T. et al., "Crystal-storing histiocytosis due to massive accumulation of charcot-leyden crystals: A unique association producing colonic polyposis in a 78-year-old woman with eosinophilic colitis", American Journal of Surgical Pathology, vol. 321, No. 3, pp. 481-485, (2007).
Lim, H.D. et al., "Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist", The Journal of Pharmacology and Experimental Therapeutics, vol. 314, No. 3, pp. 1310-1321, (2005).
Lin, R.Y. et al., "Improved outcomes in patients with acute allergic syndromes who are treated with combined H1 and H2 antagonists", Annals of Emergency Medicine, vol. 36, No. 5, pp. 462-468, (2000).
Linde, R. et al., "Combination H1 and H2 receptor antagonist therapy in mastocytosis", Annals of Internal Medicine, vol. 92, No. 5, p. 716, (1980).
Ling, P. et al., "Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation", British Journal of Pharmacology, vol. 142, pp. 161-171, (2004).
Lippert, U. et al., "Human skin mast cells express H2 and H4, but not H3 receptors", The Journal of Investigative Dermatology, vol. 123, pp. 116-123, (2004).
Liu, H. et al., "Effects of first and second generation antihistamines on muscarinic induced mucus glad cell ion transport" BMC Pharmacology, vol. 5, No. 8, pp. 1-10, (2005).
Lonnroth, I. et al., "Chlorpromazine reverses diarrhea in piglets caused by enterotoxigenic Escherichia coli ", Infection and Immunity, vol. 24, No. 3, pp. 900-905, (1979).
Lonnroth, I. et al., "Chlorpromazine reverses diarrhea in piglets caused by enterotoxigenic Escherichia coli", Infection and Immunity, vol. 24, No. 3, pp. 900-905, (1979).
Lorenz, W. et al., abstract of "Studies on the effectiveness of H1-+H2-antagonist combinations in preventing life-threatening anaphylactoid reactions in anaesthesia and surgery: Problems with selecting the animal model from clinical data and with "equi-effective" doses", Database Embase, 2 pages, (1992).
Lunardi, C. et al., "Double-blind cross-over trial of oral sodium cromoglycate in patients with irritable bowel syndrome due to food intolerance", Clinical & Experimental Allergy, vol. 21, issue 5, pp. 569-572, (1991).
Martinez, C. et al., "Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier", Gut, vol. 62, issue 8, pp. 1160-1168, (2013).
Martinez, C. et al., "The jejunum of diarrhea-predominant irritable bowel syndrome shows molecular alterations in the tight junction signaling pathway that are associated with mucosal pathobiology and clinical manifestations", American Journal of Gastroenterology, vol. 107, pp. 736-746, (2012).
Matsushita, A. et al., "Advantages of histamine H4 receptor antagonist usage with H1 receptor antagonist for the treatment of murine allergic contact dermatitis", Experimental Dermatology, vol. 21, pp. 710-720, (2012).
MedlinePlus, "H2 blockers", U.S. National Library of Medicine, National Institutes of Health, 3 pages, found at www.nlm.nih.gov/medlineplus/ency/patientinstructions/000382.htm, printed on Feb. 11, 2013.
Melcescu, E. et al., "The various faces of autoimmune endocrinopathies: Non-tumoral hypergastrinemia in a patient with lymphocytic colitis and chronic autoimmune gastritis", Experimental and Molecular Pathology, vol. 93, Issue 3, pp. 434-440, (2012).
Moscati, R.M. et al., "Comparison of cimetidine and diphenhydramine in the treatment of acute urticaria", Annals of Emergency Medicine, vol. 19, issue 1, pp. 12-15, (1990).
Murch, S., "Allergy and intestinal dysmotility-evidence of genuine causal linkage?", Current Opinion in Gastroenterology, vol. 22, issue 6, pp. 664-668, (2006).
Murch, S., "Allergy and intestinal dysmotility—evidence of genuine causal linkage?", Current Opinion in Gastroenterology, vol. 22, issue 6, pp. 664-668, (2006).
Ohsawa, Y. et al., "The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice", Allergy, vol. 67, No. 8, pp. 1014-1022, (2012).
Oksaharju, A. et al., "Probiotic lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells", World Journal of Gastroenterology, vol. 17, No. 6, pp. 750-759, (2011).
O'Sullivan, M. et al., "Increased mast cells in the irritable bowel syndrome", Neurogastroenterology and Motility, vol. 12, pp. 449-457, (2000).
Paul, E. et al., "Effect of terfenadine and ranitidine on histamine and suxamethonium wheals", European Journal of Clinical Pharmacology, vol. 34, issue 6, pp. 591-594, (1988).
Pepcid® Prescribing Information , Merck & Co., Inc., published 2000. *
Piche, T. et al., "Mast cells and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome", Gut, vol. 57, pp. 468-473, (2008).
Poli, E. et al., "Functional characterisation of the novel histamine H3 receptor agonist, VUF 5810, on the guinea-pig isolated ileum", Inflammation Research, vol. 53, supplemental 1, pp. S77-S78, (2004).
Posserud, I. et al., "Small intestinal bacterial overgrowth in patients with irritable bowel syndrome", Gut, vol. 56, pp. 802-808, (2007).
Pyleris, E. et al., "The prevalence of overgrowth by aerobic bacteria in the small intestine by small bowel culture: relationship with irritable bowel syndrome", Digestive Diseases and Sciences, vol. 57, pp. 1321-1329, (2012).
Qin, Z. et al., "Synergistic action of famotidine and chlorpheniramine on acetic acid-induced chronic gastric ulcer in rats", World Journal of Gastroenterology, vol. 11, No. 45, pp. 7203-7207, (2005).
Quigley, E. et al., "Irritable bowel syndrome: a global perspective", World Gastroenterology Organisation Global Guideline, pp. 1-20, (2009).
Rabbani, G.H., Abstract of "Mechanism and treatment of diarrhoea due to vibrio cholerae and Escherichia coli: roles of drugs and prostaglandins", Database Medline, 2 pages, (1996).
Ramos, L. et al., "Stress-mast cell axis and regulation of gut mucosal inflammation: from intestinal health to an irritable bowel", Med Clin (Barc), vol. 129, No. 2, pp. 61-69, (2007) English Abstract.
Reher, T.M. et al., "Incomplete activation of human eosinophils via the histamine H4-receptor: evidence for ligand-specific receptor conformations", Biochemical Pharmacology, vol. 84, issue 2, pp. 192-203, (2012).
Riddle, M.S. et al., "ACG Clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults", The American Journal of Gastroenterology, pp. 1-21, published online Apr. 12, 2016.
Rijnierse, A. et al., "Mast cells and nerves tickle in the tummy: Implications for inflammatory bowel disease and irritable bowel syndrome", Pharmacology & Therapeutics, vol. 116, issue 2, pp. 207-235, (2007).
Roch-Arveiller, M. et al., "In vitro effect of cetirizine on PGE2 release by rat peritoneal macrophages and human monocytes", Agents and Actions, vol. 43, pp. 13-16.
Rosenwasser, L.J. et al., "Mast cell stabilization and anti-histamine effects of olopatadine ophthalmic solution: a review of pre-clinical and clinical research", Current Medical Research & Opinion, vol. 21, No. 9, pp. 1377-1387, (2005).
Runge, J.W. et al., "Histamine antagonists in the treatment of acute allergic reactions" Annals of Emergency Medicine, vol. 21, No. 3, pp. 237-242, (1992).
Sander, L.E. et al., "Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract", Gut, vol. 55, pp. 498-504, (2006).
Schiller, L.R. et al., "Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea", Gastroenterology, vol. 92, pp. 151-160, (1987).
Schiller, L.R., "Secretory Diarrhea", Current Gastroenterology Reports, vol. 1, issue 5, pp. 389-397, (1999).
Simons, F. et al., "Effect of the H2-antagonist cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria", Journal of Allergy and Clinical Immunology, vol. 95, issue 3, pp. 685-693, (1995).
Simons, F.E. et al., "Second-generation H1-receptor antagonists", Annals of Allergy, vol. 66, No. 1, pp. 5-16, (1991).
Smith, M.J. "IBS remains a mysterious disorder, with few effective remedies", Gastroenterology and Endoscopy News, vol. 63, No. 4, pp. 1-6, (2012).
Spiegel, D.R. et al., abstract of "Treatment of irritable bowel syndrome with comorbid anxiety symptoms with mirtazapine", Database Biosis, Biosciences Information Service, vol. 34, 2 pages, (2011).
Spiller, R.C. et al., "Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute Campylobacter enteritis and in post-dysenteric irritable bowel syndrome", Gut, vol. 47, pp. 804-811, (2000).
Stacpoole, P.W. et al., "Combination H1 and H2 receptor antagonist therapy in diabetic autonomic neuropathy", Southern Medical Journal, vol. 75, No. 5, pp. 634-635, (1982).
Stokes, J.R. et al., "The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms", Journal of Allergy and Clinical Immunology, vol. 129, No. 2, pp. 409-412e2, (2012).
Sultana, N. et al., "In vitro studies of the interaction between cetirizine and H2 receptor antagonists using spectrophotometry and reversed-phase high-performance liquid chromatography", Medicinal Chemistry Research, vol. 19, pp. 462-474, (2010).
Takeshita, K. et al., "Critical role of L-selectin and histamine H4 receptor in zymosan-induced neutrophil recruitment from the bone marrow: comparison with carrageenan", The Journal of Pharmacology and Experimental Therapeutics, vol. 310, No. 1, pp. 272-280, (2004).
Thabane, M. et al., "Post-infectious irritable bowel syndrome", World Journal of Gastroenterology, vol. 15, No. 29, pp. 3591-3596, (2009).
Theoharides, T.C. et al., "Critical role of mast cells in inflammatory diseases and the effect of acute stress", Journal of Neuroimmunology, vol. 146, pp. 1-12, (2004).
Theoharides, T.C. et al., "Irritable bowel syndrome and the elusive mast cells", American Journal of Gastroenterology, vol. 107, No. 5, pp. 727-729, (2012).
Thonhofer, R. et al., "Mastocytic enterocolitis as a rare cause of chronic diarrhea in a patient with rheumatoid arthritis", Wiener klinische Wochenschrift, vol. 123, pp. 297-298, (2011).
U.S. Appl. No. 15/257,674, filed Sep. 6, 2016.
Valent, P. et al., "Standards and standardization in mastocytosis: consensus statements on diagnostics, treatment recommendations and response criteria", European Journal of Clinical Investigation, vol. 37, No. 6, pp. 435-453, (2007).
Valent, P., "Mast cell activation syndromes: definition and classification", Allergy, vol. 68, pp. 417-424, (2013).
Varga, C. et al., "Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat", European Journal of Pharmacology, vol. 522, issues 1-3, pp. 130-138, (2005).
Visser, J. et al., "Tight junctions, intestinal permeability, and autoimmunity celiac disease and type 1 diabetes paradigms", Annals-New York Academy of Sciences, vol. 1165, pp. 195-205, (2009).
Visser, J. et al., "Tight junctions, intestinal permeability, and autoimmunity celiac disease and type 1 diabetes paradigms", Annals—New York Academy of Sciences, vol. 1165, pp. 195-205, (2009).
Vivinus-Nebot, M. et al., "Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells", American Journal of Gastroenterology, vol. 107, pp. 75-81, (2012).
Wald, A. et al., "Pathophysiology of irritable bowel syndrome", UpToDate, 13 pages, Mar. 2016.
Walker, M.M. et al., "Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia", Alimentary Pharmacology & Therapeutics, vol. 29, pp. 765-773, (2009).
Walker, M.M. et al., "Implications of eosinophilia in the normal duodenal biopsy-an association with allergy and functional dyspepsia", Alimentary Pharmacology & Therapeutics, vol. 31, pp. 1229-1236, (2010).
Walker, M.M. et al., "The role of eosinophils and mast cells in intestinal functional disease", Current Gastroenterology Reports, vol. 13, issue 4, pp. 323-330, (2011).
Walker, M.M. et al., "Implications of eosinophilia in the normal duodenal biopsy—an association with allergy and functional dyspepsia", Alimentary Pharmacology & Therapeutics, vol. 31, pp. 1229-1236, (2010).
Wood, J.D., "Histamine, mast cells, and the enteric nervous system in the irritable bowel syndrome, enteritis, and food allergies", Gut, vol. 55, No. 4, pp. 445-447, (2006).
Zhang, L. et al., "Mast cells and irritable bowel syndrome: From the bench to the bedside", Journal of Neurogastroenterology and Motility, vol. 22, No. 2, pp. 181-192, (2016).

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